The aim of this NIMH Mentored Patient-Oriented Research Career Development Award application is to support my career objective to become an independent investigator specializing in the relationship between neurobiological mechanisms and clinical features of depression. My previous training focuses on phenomenological and treatment studies in mood disorders. Studies suggest that HPA dysregulation influences the presentation of depression related to melancholic and atypical symptom dimensions. A better understanding of the mechanisms underlying these differences could lead to novel targets for the treatment of depression, and help to explain variability among neuroendocrine studies that typically included heterogeneous samples with regard to depressive subtypes. Toward this end, I have proposed a training plan that includes obtaining expertise in the neurobiology of HPA dysregnlation in depression, statistical design and analysis of studies integrating biological and clinical data, and human research ethics. The research plan includes assessing HPA activity and measures of acute stress responses in healthy volunteers and depressed patients as they relate to melancholic and atypical symptom dimensions. The hypothesis is that elevated HPA axis activity in depression is associated with hyperarousal and anorexia in melancholia, whereas low HPA activity is linked with fatigue and hyperphagia in atypical depression. Moreover, increased HPA activity and melancholic symptoms are hypothesized to correlate with greater response to the Trier Social Stress Test (TSST), whereas low HPA activity and atypical symptoms are hypothesized to correlate with a decreased stress response to the TSST. These hypotheses will be tested by collection of 24-hour urinary free cortisol, and plasma cortisol and ACTH levels in depressed patients in three separate conditions: one-hour serial collections in the morning and evening; after a neuroendocrine challenge used to assess central HPA drive (DEX/CRH test); and in response to the TSST. This study will be conducted in two highly productive research settings, the Biological Psychiatry and Bipolar and Psychotic Disorder Research Programs of the University of Cincinnati Dept. of Psychiatry. The proposed training and research plans will foster my development as an independent researcher in the areas described above, and increase our understanding of the neurobiology related to the symptom profiles associated with depressive subtypes.